Examples of progress made during the prior year are summarized below. 1) We compared in monkeys and humans two radioligands that may be able to measure inflammation in the brain and found that our more recently developed radioligand has much greater specific signal (Kreisl et al., NeuroImage, 2010). Translocator protein (18-kDa) (TSPO) is highly expressed in the mitochondria of phagocytic inflammatory cells, including reactive astrocytes and activated microglia in brain. Because of high expression in these cells, positron emission tomographic (PET) imaging of TSPO, formerly called the peripheral benzodiazepine receptor, can localize inflammation in brain. For example, the TSPO-selective PET radioligand 11C-(R)-PK 11195 has been used for more than two decades to identify areas of brain inflammation in several neurological diseases. Unfortunately, 11C-(R)-PK 11195 seems to have a low ratio of signal to noise - i.e., a low ratio of specific to nonspecific binding. Measured without correction for peripheral clearance, only about 50% of 11C-(R)-PK 11195 uptake in monkey brain is specific (i.e., displaceable). We recently developed what appeared to be an improved radioligand, 11CPBR28, to image TSPO. In this study, we found that, in comparison to the prototypical radioligand, our new radioligand provides several fold greater specific binding. We will use this radioligand to examine inflammation in brain associated with Alzheimers disease and HIV infection. 2) We demonstrated that our PET radioligand, 11C-desmethyl-loperamide (a metabolite of Imodium), can measure the function at the human blood-brain barrier of a transporter that may be involved in drug resistance in epilepsy and in HIV infection of brain (Kreisl et al., J. Nucl. Med., 2010). Permeability-glycoprotein (P-gp), an efflux transporter in several organs, acts at the blood-brain barrier to protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the positron emission tomographic (PET) radiotracer 11C-N-desmethyl-loperamide (11C-dLop). We examined the ability 11C-dLop to quantify P-gp function in humans after increasing doses of tariquidar, an inhibitor of P-gp. We found that P-gp function at the blood-brain barrier in humans can be quantified using PET and 11C-dLop. A simple measure of brain uptake may be used as a surrogate of the fully-quantified rate constant for brain entry and thereby avoids arterial sampling. These results suggest that 11C-dLop can quantify P-gp function in diseases hypothesized to have abnormal activity of this efflux transporter, whether in the periphery (e.g., multidrug resistance cancer) or at the blood-brain barrier (e.g., epilepsy and Alzheimers disease). 3) We developed and evaluated a novel PET radioligand to measure the cannabinoid CB1 (marijuana) receptor in human brain (Terry et al., J. Nucl. Med, 2010). The CB1 receptor is associated with several neuropsychiatric disorders, including alcoholism and schziophrenia. We recently reported that the PET radioligand 11C-MePPEP can image and quantify cannabinoid CB1 receptors in human brain. This radioligand has such high and stable uptake in brain that it can be meaningfully imaged for 210 min after injection, and receptor density can be quantified using the gold standard of compartmental modeling with an arterial input function. Nevertheless, 11C-MePPEP was limited by its short radioactive half-life (20 min), not because of low radioactivity in brain, but because of low radioactivity in arterial plasma. A PET radioligand using a radionuclide with a longer half-life (e.g., 18F, 110 min) would provide for extended measurements from arterial plasma and hopefully allow more accurate quantitation of CB1 receptors in brain with compartmental modeling. We recently synthesized three 18F-labeled analogues of MePPEP: 18F-FEPEP, 18F-FMPEP, and 18F-FMPEP-d2. The purposes of the present study were to compare the brain uptake of these three analogs in monkey and to evaluate the most promising candidate in humans. This initial evaluation of 18F-FMPEP-d2 in healthy human subjects showed that brain uptake and unchanged parent radioligand in plasma provide robust measurements of distribution volume, which is an index of receptor density. This radioligand seems ideal to examine in live subjects changes in CB1 receptors that been previously shown in animals and postmortem studies. These disorders include marijuana abuse, alcoholism, and schizophrenia